In the development of pharmaceuticals, simultaneously with the development of novel compounds having excellent pharmacological effects, various investigations have been made into changes of the dosage forms and an optimization of the administration forms, to to further enhance the effects of these novel compounds or compounds already used as pharmaceuticals.
For example, to prolong the persistency time of a pharmaceutical with a short half-life period, which is also a parameter of the effective persistency time of a pharmaceutical in the body, the development of slow release preparations has been made, which will enable the pharmacologically effective ingredient to be absorbed by the human body at the minimum effective level or higher and the maximum safe level or lower, i.e., in the effective level region in the blood, over a long time.
As examples of slow release preparations, there are known preparations for a percutaneous absorption such as ointments, sprays and coatings. These preparations are coated by hand onto the skin, and therefore, the dose is not constant, and further, a problem arises in that the ointment may adhere to and contaminate the clothing of the patient.
As measures for alleviating these drawbacks, there are known tape agents and plaster agents which incorporate a predetermined amount of a medicine and are molded to a predetermined size (e.g., see Japanese Unexamined Patent Publications (Kokai) Nos. 57-116011, 58-134020), and the use of the method using the tape agent and plaster agent can solve many problems due to the use of an ointment or spray coating.
Also, when a medicine is percutaneously administered, it is known that the ratio of the liver metabolism, which is the phenomenon whereby the pharmacological effect disappears upon receiving the metabolism of the drug in the liver, can be markedly alleviated compared with the case when the medicine is orally administered, and therefore, a tape agent and plaster agent (hereinafter referred to as plaster agent) is an excellent medicine administration form when the medicine can be percutaneously absorbed.
Nevertheless, frequent use of such a plaster agent has shown that some problems arise with the plaster agent of the prior art.
Among such problems, the most frequent is a skin rash generated at the site at which the plaster agent is plastered to a patient. Generally speaking, a sustained release preparation is frequently administered to a patient with chronic diseases, and therefore, the plaster agent is frequently used over a long term, and thus a skin rash is often generated. Further, a problem arises in that, once a skin rash is generated, the afflicted site is susceptible to a growth of the rash. According to statistics, the generation of a skin rash by a plaster agent occurs in 20 to 50% of all patients.
Another problem of the plaster agent is a change of the medicine level in the blood. The factors causing a change of this level in the blood are complicated, and include the plaster agent, the skin, and the human metabolism functions, and therefore, it is not easy to hold the medicine level in the blood at a constant value.
Still another problem concerns the handleability. More specifically, a skin rash could be more or less alleviated by making the support of the plaster agent as thin as possible, enhancing the flexibility, and making the plaster agent smaller to alleviate a skin rash caused by the plaster, but another problem arises in that it is very difficult to plaster the plaster agent correctly at a predetermined position on the patient. For example, recently, plaster agents containing as an effective component nitric acid esters are widely used as therapeutic agents for circulatory diseases such as stenocardia, but the above-mentioned various problems, particularly the skin rash problems, still remain and, therefore, plaster agents capable Of stably maintaining the concentration of medicines in the blood and not having the above-mentioned problems are needed in this field.
On the other hand, as the cause of menopausal disorders, oestoroporosis, and Arzheimer dementia, frequently observed in women after menopause, a reduction of estrogen accompanying the menopause is regarded as important, and estradiol, estriol and derivatives thereof have been clinically applied primarily as oral agents and injections.
When estrogen is frequently used, however, side effects such as an increase in an uterus body cancer are observed, and therefore, it is necessary to enhance the biological availability (hereinafter abbreviated as BA) during use, as much as possible, at a minimum necessary dose, while maintaining a stable medicine level in the blood.
Among various estrogens clinically applied, estradiol is one of the natural estrogens which are inherently synthesized and utilized in the living body, has a pharmacologically high activity, and although considered to be the most suitable estrogen for use as a pharmaceutical from the aspect of safety, it has been little used. This is because estradiol, when administered orally, is rapidly metabolized in digestive organs and the liver and the BA is lowered. To maintain the necessary drug level in the blood, a large amount of estradiol must be administered, but this means that an undesirable larger amount of harmful metabolites by products will be produced in the blood.
The loss of the BA in estradiol can be markedly ameliorated by a percutaneous administration, and a stable drug level in blood can be still maintained.
Estradiol and derivatives thereof such as esters are known to be percutaneously absorbed, as disclosed in Japanese Patent Publication (Kokoku) No. 46-5427, Japanese Unexamined Patent Publication (Kokai) No. 57-154122, etc. Particularly, the plaster agent disclosed in Japanese Unexamined Patent Publication (Kokai) No. 57-154122 provides an excellent improvement of the BA and stabilization of the drug level in the blood. Nevertheless, although the estradiol-containing plaster agent compensates for a reduction of estrogen accompanying the menopause, the therapeutical period can last for several months to several years, and therefore, a steadfast compliance by the patient is an essential requirement. Particularly, in the presence of a plaster agent, although an uncomfortable feeling during plastering often exists, a generation of a skin rash is a serious problem, an insufficient consideration of this point has been made in the prior art.
In the prior art as described above, in the case of an oral agent, which requires a relatively lower compliance by the patient, the BA is lower and a generation of side effects is a serious problem, but in the case of a percutaneous absorption type plaster agent with a high BA and a stable medicine level in the blood, the problems of discomfort and a generation of skin rash remain.
To alleviate the feeling of discomfort, which is a drawback of the prior art, preferably the flexibility of the plaster agent is enhanced as much as possible and the size thereof made smaller. If the flexibility is made too high, however, the handling of the plaster agent will become very difficult and will reduce the practical applicability thereof. On the other hand, since the size of the plaster agent is proportional to the amount of medicine absorbed, i.e., the medicine level in the blood, if the necessary medicine level in the blood is determined, some means for enhancing the percutaneous absorbability is essential when making the size of the plaster agent smaller. Accordingly, if an absorption promoter is used for enhancing the percutaneous absorbability of the medicine, a problem arises in that a skin rash will occur more frequently. On the other hand, to alleviate the skin rash, the prior art has investigated a suitable selection of the tackifier and a reduction of a residual monomer or residual solvent in the tackifier, but fundamentally it is preferable to enhance the water vaporizability or gas permeability of oxygen .and carbon dioxide of the plaster agent. The mere enhancement of the water vaporizability or gas permeability of the oxygen, however, may reduce the sealability of the plaster agent, and thus reduce the percutaneous absorbability of the medicine.
It is considered that 80% of patients at the late stage of cancer suffer unendurable pain, and currently 50 to 80% thereof are receiving therapy for a removal of the pain.
Recently it is considered that late stage cancer patients, substantially without hope from therapy, should pass their remaining time at home with their families, and accordingly, an analgesic which can be easily administered, has a required effect, and causes little side-effects has been developed.
Generally speaking, a therapy of pain is practiced for three ranks of the WHO cancer pain ladder. Namely, when pain is generated, first a non-opium type analgesic is used, and when this is not sufficient, a weak acting opium type narcotic is used, and when even that is not effective, a strong opium type narcotic is used. The unendurable pains experienced by patients at the late stage of cancer are included in the second step and the third step, and as the drug therapeutical method for a therapy thereof, .opium type narcotics are employed.
A representative weak opium type narcotic drug is codeine, and a representative strong opium type narcotic drug is morphine. The strength of the action thereof determines whether the drug is a weak opium type or a strong opium type, but various side effects are also taken into consideration. The side effects of opium type narcotics include nausea, vomiting, sleepiness, constipation, and mental disorders, and further, a drug resistance or habit occurs and diminishes the effects thereof during usage. In view of the seriousness of such side effects, even if the analgesic effect of such an opium type narcotic is high, the use thereof must be carefully considered under the present situation.
To solve these problems of opium type narcotics, attempts to alleviate the side effects by enhancing the analgesic effect by a chemical modification of the opium type narcotics have been made for many years.
One of the synthetic analgesics developed from such an investigation is buprenorphin. Bupurenorphin is known to have an analgesic effect 25- to 50-fold of that of morphine, and to exhibit little side effects such as mental disorders, etc. Buprenorphin is commercially available as an injection in this country, and suppositories have been also developed. Further, in other countries, sublingual tablets are commercially available. Investigations into the development thereof as an ointment have been also made.
Nevertheless, in the preparations of the prior art, problems arises in that the number of administrations is very high, and thus a recurrence of the pain begins unless the medicine is administered at a correct time, and further, the administration method is cumbersome. Also, according to the administration method of the prior art, the change in the drug level in the blood is great.
Buprenorphin is a preferable medicine with less side effects than morphine, but side actions similar to morphine will be generated by a continuous usage thereof over a long term.
The mechanism of the generation of side effects has not been clarified, but in view of the dose dependency, it is not preferable to enhance the level in the blood more than is necessary. If continuously used for a long term under the state in which the level in blood becomes higher than is necessary, not only is there an increased probability of this leading to serious side effects, but also there is a fear that, even within a short term, a serious side effect such as respiration suppression may be induced.